Human apolipoprotein (apo) E, a 34-kDa protein with 299 amino acids, has three major isoforms, apoE2, apoE3, and apoE4 (1-4). apoE4 is a major risk factor for Alzheimer's disease (AD) (5-7). The apoE4 allele, which is found in 40-65% of cases of sporadic and familial AD, increases the occurrence and lowers the age of onset of the disease (7, 8).
Biochemical, cell biological, transgenic animal, and human studies have suggested several potential mechanisms to explain apoE4's contribution to the pathogenesis of AD. These include modulation of the deposition and clearance of amyloid beta (Aβ) peptides and the formation of plaques (9-15), modulation of Aβ-caused synaptic and cholinergic deficits (16), acceleration of age- and excitotoxicity-related neurodegeneration (17), impairment of the antioxidative defense system and mitochondrial function (18-21), dysregulation of neuronal signaling pathways (22), altered phosphorylation of tau and neurofibrillary tangle formation (23-28), depletion of cytosolic androgen receptor levels in the brain (29, 30), potentiation of Aβ-induced lysosomal leakage and apoptosis in neuronal cells (31), and promotion of endosomal abnormalities linked to Aβ overproduction (32-34). The mechanisms of these apoE4-mediated detrimental effects are largely unknown.
It has been shown that apoE can be cleaved by a neuron-specific chymotrypsin-like serine protease that generates bioactive carboxyl-terminal-truncated forms of apoE (25, 27, 28). The fragments are found at higher levels in the brains of AD patients than in age- and sex-matched controls (27), and apoE4 is more susceptible to cleavage than apoE3. When expressed in cultured neuronal cells or added exogenously to the cultures, apoE4 fragments are neurotoxic, leading to cell death (25). When expressed in transgenic mice, they cause AD-like neurodegeneration and behavioral deficits (27).
Alzheimer's disease is an insidious and progressive neurological disorder for which there is currently no cure. In view of the lack of adequate treatment for Alzheimer's disease, there exists a need for novel treatment methods for this neurological disorder. The instant invention provides methods of identifying agents for use in treating disorders relating to apoE4.
Literature
    Huang et al. (2001) Proc. Natl. Acad. Sci. USA 98:8838-8843; U.S. Pat. No. 6,046,381.